Parathyroid hormone decreases endothelial osteoprotegerin secretion: role of protein kinase A and C.
Parathyroid hormone (PTH), which is elevated in patients with chronic renal failure, has been shown to participate in the development of vascular calcification. Previous studies have demonstrated that PTH may promote endothelial expressions of proinflammatory parameters. On the basis of these data, we evaluated whether PTH may have an impact on endothelial osteoprotegerin (OPG), a vascular-protective factor which may control vascular calcification. Endothelial cells were stimulated with 10(-12) to 10(-10) mol/l PTH. PKC and PKA are the main cellular pathways of PTH. Inhibitors and activators of PKC or PKA were used to determine whether these signaling pathways are involved in the control of endothelial OPG. PTH induced a decrease in OPG secretion and mRNA expression. Treatment of PTH-stimulated cells by calphostin C (PKC inhibitor) induced a further decrease in OPG secretion, while Rp-cAMP (PKA inhibitor) had no additional effect. In nonstimulated cells, a PKC activator significantly stimulated OPG secretion, while a PKA activator was associated with a decline. These effects were blunted in the presence of calphostin C and Rp-cAMP, respectively. An increase in OPG secretion induced by a PKC activator indicates that the basal OPG secretion is mediated through PKC. The decrease induced by a PKA activator, which is similar to the decrease observed with PTH, suggests that the action of PTH on OPG secretion and mRNA expression may be due to the PKA pathway.
Rashid
Gloria
G
Dept. of Nephrology and Hypertension, Meir Medical Center, Kfar-Saba, Tchernichovsky 59, Kfar-Saba 44281, Israel. Gloriar@clalit.org.il
Plotkin
Eleanora
E
Klein
Osnat
O
Green
Janice
J
Bernheim
Jacques
J
Benchetrit
Sydney
S
D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology; D053244:Osteoprotegerin / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D009281:Naphthalenes; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C058819:calphostin C